Nausea and vomiting caused by chemotherapy remain among the most distressing side effects for patients undergoing treatment for cancer. Depending upon the chemotherapy agents or regimens given, up to 90% of patients may suffer from some form of chemotherapy-induced nausea and vomiting (CINV). Symptoms from CINV can be severely debilitating and often result in patients refusing further courses of chemotherapy, with obviously unfavorable consequences with respect to progression of the cancer. Furthermore, CINV is burdensome on the medical system, consuming time from the healthcare staff, who could otherwise attend to other patients or medical issues.
CINV is divided into two main categories: acute CINV and delayed CINV. Acute CINV occurs within the first 24 hours of treatment; delayed CINV occurs from 24 hours to 120 hours following treatment. Delayed CINV remains a highly under-treated side effect in patients undergoing chemotherapy, as healthcare providers tend to underestimate the number of patients who suffer from delayed CINV. Furthermore, delayed CINV greatly impairs patients' ability to provide care to themselves once they have been discharged.
Compounds that inhibit serotonin receptors are currently the most effective antiemetics; they constitute the single greatest advance in the management of nausea and vomiting in patients with cancer and have had additional application in radiation-induced nausea and vomiting (RINV) and post-operative nausea and vomiting (PONV). Blocking the 5-HT3 receptor from the serotonin signal produced from chemotherapy-induced damage to the gut's enterochromaffin cells, which house the majority of the body's serotonin reserves, via either a peripheral or central mechanism appears to prevent acute emesis. Except for palonosetron (Aloxi®), 5-HT3 inhibitors have been approved for and most effective against the treatment of acute CINV. Palonosetron, which must be given intravenously, is the only 5-HT3 inhibitor currently approved for the prevention of both acute and delayed CINV. The efficacy of palonosetron against delayed emesis has been postulated to be due to its long serum half-life. Therefore persons of skill in the art accept that 5-HT3 inhibitors that have long serum half-lives will be effective therapeutic agents for both acute and delayed CINV; those that have short half-lives will be useful to treat acute CINV. In addition, the combination of palonosetron, a 5-HT3 inhibitor, and aprepitant (EMEND®), a neurokinin antagonist, has been shown to be highly effective in preventing both acute and delayed CINV following a variety of moderately to highly emetogenic chemotherapy regimens in clinical trials. Notably, combination therapy of either NK1 antagonists or 5-HT3 antagonists with corticosteroids such as dexamethasone, improve the performance of these drugs against acute or delayed emesis. To that point, EMEND® labeling indicates that the drug is dosed with a corticosteroid and a 5-HT3 antagonist.
Irritable Bowel Syndrome (IBS) generally occurs in three types: diarrhea predominant (IBS-D), constipation predominant (IBS-C) and IBS with alternating symptoms termed IBS-A or mixed-mode (IBS-M). Diarrhea predominant Irritable Bowel Syndrome is a debilitating, though seldom fatal, disease. The typical sufferer of IBS-D exhibits primary symptoms including multiple and daily explosive diarrhea attacks and severe daily abdominal cramps. The most common secondary side effects include panic attacks, depression, withdrawal from social and family activities and malnutrition.
At present, compounds that inhibit 5-HT3 receptors are the only effective treatment for IBS-D. The only drug currently approved for IBS-D is alosetron, which was introduced by Glaxo, withdrawn by the FDA because it appeared to cause ischemic colitis, then reinstated by the FDA because the demand was so great for some treatment for IBS-D. In 2002, the US Food and Drug Administration approved alosetron hydrochloride (LOTRONEX®) tablets under restricted conditions for women in whom the medical benefits outweigh the risks. The restrictions on the approval reflect the serious gastrointestinal adverse events that have been reported with the use of alosetron. A second structurally related 5-HT3 inhibitor, cilansetron, had been making its way through clinical trials and recently received a non-approvable letter from the FDA. New, structurally unrelated 5-HT3 inhibitors may be useful for the treatment of IBS-D.
Clearly there is a need for improved therapy for both CINV and IBS-D.